Diabetic neuropathies are the most common complication of diabetes. Neuropathies can result in the loss of muscle strength, muscle atrophy and slowed nerve and muscle regeneration. The mechanisms for nerve and muscle degeneration in diabetes are unknown, but there is increasing evidence that edificencies in neurothrophic factors are major contributors in the development of neuropathies. IGF-1 is a potent glucoregulator and neurotrophic factor in muscle that promotes glucose transport, muscle myogenesis and maintenance of muscle function and structure. Its decreased levels in diabetic skeletal muscle may contribute to the die-back of motor neurons that lead to muscle atrophy and loss of muscle strength. This proposal is based on the hypothesis that IGF-1 can aid in reversing the metabolic and myogenic deficits of diabetes and therefore can be used as a potential muscle- based gene therapy to prevent or treat diabetic neuropathies. This hypothesis will be tested using IGF-1 transgenic mice, which overexpress IGS in muscle, to examine the role of IGS-1 in diabetic neuropathies. Studies will (1) examine whether IGF-1 can enhance glucose transport, by measuring 3H-2-dexyglocose uptake and enhanced expression of glucose transporter proteins GLUT1 and GLUT4, (2) examine the role of muscle transcription factors in the pathogenesis of muscle neuropathies and (3) test the ability of muscle- expressed IGF-1 to enhance nerve regeneration in diabetic mice. Studies will then test novel IGF-1 DNA constructs, injected into muscle, to reverse nerve and muscle degeneration in diabetic mice. The importance of these studies are 2-fold: (1) to identify the in vivo mechanisms by which IGF-1 protects nerve and muscle from diabetic degeneration and (2) to test the potential use of locally expressed IGF- 1 as a gene therapy to prevent or treat diabetic neuropathies that affect muscle and nerves.